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[ RESEARCH 35, 3292-3300November 1975]

Nutrition and Experimental : A Review'

David B. Clayson

Eppley Institute for Research in Cancer, University of Nebraska Medical Center, Omaha, Nebraska 68105

Summary considerably modify the response of experimental animals in carcinogenicity tests. Restriction of the total diet or the number of calories fed Changes in tumor incidence may also be brought about to rats and mice inhibits the formation of tumors in several by altering the composition of the diet. In some cases, tissues. Unless animals are fed equivalent levels of , or especially in that of chemical , there is knowl attain equivalent body weights, it is difficult to assess the edge of the mechanism by which these changes arise. significance of the effect of other nutritional modifications Modifications of the metabolic activation of carcinogens by on carcinogenesis. The effects of altering the levels of controlling the levels of cofactors or by inducing different protein or fat are much less than those seen with dietary patterns of metabolizing activities are well docu restriction. Feeding a protein-free diet is tolerated for a mented. On the other hand, those factors which regulate limited period and can alter the of carcinogens. tumor development, such as different levels of cellular It may thus affect the tumor incidence induced by one-shot proliferation or immunological control, do not appear to carcinogens. Vitamins have specific effects on the activity of have been as amenable to study. certain carcinogens, the fullest information being available This presentation will illustrate the way in which nutni for vitamin A, which has been shown to inhibit or enhance tional differences can affect tumor incidence in experimen carcinogenesis, and vitamin C, which by reducing sodium tal systems. Wherever possible, the mechanism by which , prevents nitrosation of secondary and tertiary these changes are mediated will be discussed. amines occurring in acidic conditions of the stomach. Inorganic substances, such as iodine (thyroid) and copper Dietary and Caloric Restriction (liver), may affect the tumor incidence in specific tissues. The metabolic activation of carcinogens is modified by The demonstration from actuarial records that over enzyme induction and the administration of antioxidants. weight or obese men had a higher cancer mortality than The relevance of these results to the induction of cancer in normal or underweight men led Tannenbaum (93) to humans is briefly discussed. investigate the effect on the development of spontaneous and induced tumors of a restricted dietary intake in mice. Introduction Dietary restriction reduced the incidence of mammary tumor -induced tumors in DBA and C3H mice, Carcinogenesis may be affected by nutrition in 2 ways. spontaneous tumors in Swiss and ABC mice, B(a)P Food or drink may be contaminated by carcinogens, or the induced tumors and, to a lesser extent, s.c. composition of the diet may impose upon the host patterns induced by B(a)P (Chait 1) (94, 95). Similar effects have of enzyme activity and other factors that dictate the yield of been observed in rats. As in mice, underfeeding greatly naturally occurring or induced tumors. The deliberate increased the life-span (45) and led to a lower tumor addition of carcinogenic additives to food should diminish, incidence than that found in animals that received ad as a result of worldwide governmental action. Nevertheless, libitum supplements 74, 80). In these underfeeding studies, the control of naturally occurring carcinogens in food the amounts of the various dietary components were presents difficulties, especially for technically developing reduced proportionately to each other. countries. The most studied naturally occurring carcinogens An alternative to underfeeding is caloric restriction, in include B1 and G1, , and other which the amount of is reduced, while other (40). There is presumptive evidence that components are maintained at a constant level. Calorie aflatoxins are carcinogenic in humans (67). Also to be restricted diets also lessen the incidence or delay the considered are the carcinogens present in bracken fern appearance of certain tumors, such as mammary tumors in (20—22,64), cycasin (42), the , especially those DBA mice (Chart 2) (97). In this example, the inhibition formed from nitrite and secondary or tertiary amines (53, was apparent, even if the restricted diet was not instituted 79), environmental goitrogens, and hormones, and other until the mice were 9 months old. dietary carcinogens. Besides their possible carcinogenic The mechanism by which dietary restriction inhibits actions in man, the presence of these substances may 2 The abbreviations used are: B(a)P, benzo(a)pyrene; DAB; 4-dimeth ylaminoazobenzene; DMN, dimethylnitrosamine; MCA, 3-methylcholan CPresentedattheConferenceonNutritionintheCausationofCancer, threne; DMBA, 7,l2-dimethylbenz(a)anthracene;FAA, N-2-fLuorenyl May 19 to 22, 1975, Key Biscayne,Fla. Supported by Contract NOI acetamide;BHA, butylated hydroxyanisole; BHT, butylated hydroxytol CP33278from the National Cancer Institute, NIH, USPHS. uene.

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U) mediated through its effect on body weight. They suggested 0 that the inhibition of tumorigenicity is associated with an D I-. overall nutritional deficiency at the cellular level, but did not

0 Mammary speculate as to the nature of the process. Whatever the SkinTumors explanation of these observations, they are crucial to all 30— (24 weeks) (24 weeks) (86weeks) aspects of experimental tumorigenesis. Experiments de @2O— fl signed to show anything more than the crudest tumor-induc @l:1@J@ L1= EL ing potency of a strong must be carried out in such a manner that all experimental and control groups @ :@ DIETadIsbitum maintain similar body weights. Experiments that fail to @@ RestrictedDIET adhere to this principle are difficult to interpret. Factors Chart I . The effect of restricting caloric intake on the incidence of that may to decreased body weight in treated animals sarcomas and skin tumors induced by B(a)P and on naturally occurring include chemical , unpalatability of the diet, and mammary tumors in DBA mice (95). chronic ill in the colony. Good experimentation can overcome these difficulties. Because the influence of dietary and caloric restriction was not realized until 1940, work in 00 nutrition and cancer carried out before that time is difficult to interpret. 80 U z U a Protein Levels U -p z g 2 A MAMMARY-DBAQMICE The feeding of isocalonic diets containing levels of protein I- B SKIN-B(a)P INDUCED 1e 20- C MAMMARY-C3H9MICE ranging from 9 to 45% failed to influence the incidence of 0- - mammary tumors in DBA and C3H mice, and that of -induced skin tumors and s.c. sarcomas. Spon ‘ 0 II 2 3 14 CALORIC INTAKE per DAY taneous hepatomas in C3H mice occurred less frequently Chart 2. The effect of caloric restriction on mammary tumor induction when the 9% protein diet was fed (100). This was due to a in C3H and DBA mice and on skin tumors inducedby B(a)P (98). diminution in the concentration of the essential sulfur-con taming amino acids, cysteine and methionine. The addition of sufficient protein, freed from these amino acids, to raise tumonigenesis is unknown. Initiation-promotion studies in the protein level from 9 to 18%, failed to affect the incidence skin carcinogenesis were said to show that restriction was of spontaneous hepatomas, whereas addition of the calcu effective in the promotion or developmental stage of tumor lated amounts of these amino acids did so (88). formation, but some influence on the initiation stage could High protein levels, however, protect the rat liver against not be excluded by the data presented (Table 1) (97). The carcinogenesis by DAB. Adequate dietary casein, even with yield of mammary tumors was not affected by starving low levels of riboflavin (see below) protects the rat liver DBA. mice for 2 periods of 24 hr each week and permitting against this chemical. The reason for this phenomenon is them to eat ad libitum for the remaining time. These mice not known. Tannenbaum and Silverstone (104) suggested consumed as much as those fed ad libitum continuously that the high-protein diet might be protective because it (101). The actual number of calories is not necessarily enabled the liver to store and utilize riboflavin more significant, because mice fed thyroid extract consumed 1.5 efficiently. times the normal amount, while maintaining a slightly lower Ross and Bras (75) fed diets containing 10, 22, or 51% than average body weight. The yield of tumors induced by casein on either a restricted (equicaloric) or an ad libitum painting B(a)P on the skin was unaffected by thyroid extract (85). Other treatments, which did not involve reduction of Table I caloric intake and reduced body weight, included maintain The dependenceof the genesisof induced skin tumors on the caloric ing the mice in a cold environment (7.2—12.8°)or feeding intake during different stages of carcinogenesis° them dinitrophenol or sodium fluoride. Each of these Diet50-wkGrouplO-wk treatments significantly inhibited naturally occurring mam mary tumors in DBA mice. The chemicals blocked forma tion of lung but had little effect on B(a)P-induced sarcomas, while dinitrophenol showed little influence on painting ment of tumorsIPF49692FR50343RR50244RF5055perioddevelop periodNo. mice% B(a)P-induced skin tumors (99). Gold thioglucose induces a specific hypothalamic lesion in mice which causes severe through an increase in adipose tissue, leading to a doubling of the body weight. A high incidence of mammary tumors were obtained in these animals (113). Tannenbaum and Silverstone (104) concluded that the aFromRef.95 relevant effect of dietary or caloric restriction was probably a F, full diet; R, restricted diet.

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Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 1975 American Association for Cancer Research. D. B. Clayson regimen to rats. Longevity increased from the group of rats induction of esophageal (107) or nasal epithelial tumors fed 10% casein ad libitum to that fed 5 1% casein restricted, (62). and tended to increase with the amount of protein in the The possibility that protein from various sources may diet. The most common tumor in the high-protein groups influence carcinogenesis has not been studied. It may be was of the urinary bladder (Table 2). Urinary minimal in view of the hydrolysis of protein to amino acids stone formation was not described ( I3). Possibly, this is an before ingestion. Such experiments are required to assess effect of the increase in the amount of the essential amino the significance, for example, of beef consumption in the acid tryptophan administered in the protein. It has been etiology of human colon cancer (2). suggested that the urinary output of those tryptophan metabolites on the niacin pathway is higher in some patients Lipotrope Deficiency with nonoccupational than in normal sub jects (9, 68). Furthermore, feeding a 7-fold excess of Lipotropic substances are those which prevent or correct DL-tryptophan to dogs led to of the urinary fatty liver due to choline deficiency. Lipotrope-deficient bladder (69). An increase in the proliferation of the rat diets are low in choline and methionine. Choline-deficient bladder epithelium has been reported on a similar regimen diets per se in rats, and in chickens surviving beyond 78 (56). The metabolites of tryptophan responsible for these weeks, led to fatty livers and to liver tumors (17, 78). More effects have not been identified. They might be N-hydrox recent confirmation of the latter result is lacking (58), and ylated derivatives of the amino acid and its metabolites. The the possibility cannot be excluded that the liver tumors were previously suggested o-aminophenol derivatives (68), which a consequence of the interaction of the hepatotoxic diet (59) have, as yet, given little satisfactory evidence of biological and adventitious contamination with a natural carcinogen, activity in the bladder, are unlikely to be the carcinogenic such as B1. Nevertheless, there is evidence that factor. lipotrope-deficient diets enhance hepatoca rcinogenesis by Very low levels of protein can be sustained for short , diethylnitrosamine, and DBN (58, 71). In the periods of time, but are not compatible with the survival latter 2 examples, the latent period of the tumors was required for most carcinogenesis tests. The advent of diminished. induction by diethylnitrosa single-dose carcinogens has made it possible to maintain mine was possibly also enhanced. Other tumors were not animals on a very low protein diet during administration of affected (73). The lipotrope-deficient diets have been dem the carcinogen and then return them to an adequate diet for onstrated to reduce the activity of hepatic metabolizing the remainder of their lives. Swann and McLean (92) , such as aminopyrene demethylase, p-nitroaniline showed that feeding a protein-free diet for only 7 days led to demethylase, and B(a)P hydroxylase (72), and also to a 45% inhibition of liver metabolism of DMN in vivo, but increase the mitotic rate in the liver (71). that kidney metabolism was unaffected. In liver slices, this pretreatment led to more than a 50% inhibition of metabo Lipids lism. The amount of 7-N-methylguanine formed in liver RNA and DNA was little affected by the protein-free diet, Both the amount and nature of the lipid component of the while that in the kidneys increased 3-fold. The overall effect diet may vary. The high caloric value of fat makes it of the low-protein diet was to decrease hepatoxicity and essential to feed equicalonic amounts of each diet. An early increase the dosage that is lethal to 50% of the animals, experiment in which tumors were produced by skin painting thereby enabling more chemical to be administered in a with B(a)P, MCA, or dibenz(a,h)anthracene showed that, in single dose. Thus, by giving the maximum tolerated dose, it the case of each of 5 different fats, 3 different basal rations, was possible to increase the incidence of kidney tumors and 2 strains of mice, the tumor incidence increased when induced by a single administration of DMN (30, 46, 92). the dietary level of fat exceeded 15% (35). The result could Very-low-protein diets or starvation for a limited period will have been due to the fat content of the diet, or to the protect the liver from toxic or carcinogenic chemicals, resultant higher energy content that led to increased body because they induce a general reduction in the activity of weight. Tannenbaum (96, 98) and Silverstone and Tannen microsomal metabolizing enzymes 447). No effect of very baum (86, 88) showed by using equicaloric diets that a low-protein diets or starvation has been observed in the regimen that contained enhanced levels of fat increased the

Table 2 The efftct of 10, 20, and 51% casein on longevity, spontaneous tumor incidence. and number of bladder in rats°

caseinLife casein20% casein5 1%

of of of expectancy bearing bladder expectancy bearing bladder expectancy bearing bladder papillomasAdlibitumRegimen10% (days)Tumor rats (%)No. papillomasLife (days)Tumor rats (%)No. papillomasLife (days)Tumor rats (%)No.

Restricted13a 69225.6 11.43 5585 83828.8 19.29 9614 93428.0 21.619 (equicaloric)540

From Ref. 98.

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Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 1975 American Association for Cancer Research. Nutrition and Experimental Carcinogenesis incidence of B(a)P-induced skin tumors in Swiss, C57 inhibited formation of dyskeratotic lesions, as well as Black, and DBA mice, and of naturally occurring hepato carcinomas of the forestomach and small intestine, induced mas in C3H mice. With mammary tumors in DBA mice, by DMBA and B(a)P, and against esophageal dyskeratotic either the latency was reduced or the number of tumors lesions induced by the former hydrocarbon. A considerable increased. There was no effect on s.c. or lung volume of evidence on the protective effect of dietary or induction. The positive effects were of a lower topical vitamin A on skin tumor production in mice by order than those seen with caloric restriction, which led to , often in combination with croton oil promo the suggestion that they may have been due to different tion, has been obtained (4—6, 18, 83). Shamberger (83) “energyvalues― of fat and carbohydrate and that caloric showed that topically applied fl-carotene, a vitamin A intake is an imprecise parameter in this type of work (7). precursor, which is converted to vitamin A in the intestine, The importance of the type of fat in the diet is well enhanced the incidence of papillomas induced by DMBA illustrated by the induction of hepatomas in rats fed DAB. and croton oil, whereas retinyl acetate and retinol inhibited Substitution of hydrogenated coconut oil for corn oil papilloma formation. Retinol also inhibited papillomas reduced the number of hepatomas obtained at 6 months induced by the hydrocarbon and phenol, as a promoting (50), although the more potently carcinogenic 3'-methyl agent. It was shown that lysosomal labilizers, such as derivative did not show the effect (28). The fatty acids filimarisin, a polyene antibiotic, and vitamin A, had a obtained from hydrogenated coconut and corn oils gave rise considerable protective effect, whereas the lysosomal stabil to similar tumor yields in the experiments involving DAB izers, chloroquine and hydrocortisone, enhanced the tumor (38). Other oils used in similar experiments gave variable yield. The inhibitory effect of vitamin A on carcinogenesis hepatoma yields (39, 5 1). It has been suggested that the was suggested to be due to the destabilization of the tumor-inhibitory fats enable the liver to store riboflavin lysosomes of “premalignant―cells. more efficiently and that this to the greater activity of Schmählet a!. (81) failed to demonstrate any protective detoxifying enzymes, for which riboflavin is part of a effect of vitamin A (palmitate and acid) on the induction of cofactor (52). tumors by painting B(a)P on mouse skin. This experiment Beef fat (35% of diet) enhances the yield of intestinal and another on injection site fibrosarcomas induced by the tumors induced by azoxymethane in rats (60). The body same chemical may be criticized, because the short latency weight of rats treated with this compound in normal and of the induced tumors indicates that a massive carcinogenic beef fat diets was similar, although those treated with beef stimulus was used, and that may have overridden any fat diets without carcinogen were heavier. The enhancement protective effect of vitamin A. In the hamster cheek pouch, may therefore be a direct result ofthis fat supplement, but it topical application of DMBA and vitamin A was shown to is unclear as to whether only beef fat is effective or if other induce more tumors per animal and a greater volume of fats could be substituted. Other aspects of experimental tumor tissue than the hydrocarbon alone (43). The number intestinal cancer have been discussed by Weisburger et a!. of animals used was small. (70). The effect of vitamin A derivatives on bronchial car Cycloproprenoid fatty acids may be derived from raw cinogenesis is confused. Original observations indicated that cotton seed oil or Sterculiafoetida oil. These substances act dietary retinyl palmitate inhibited induction of lower respi as cocarcinogens in hepatocarcinogenesis by aflatoxin B1 in ratory tract tumors by B(a)P and ferric oxide dust in the rats (61, 89). The effect on diethylnitrosamine carcinogene hamster (77), but a recent experiment has produced an sis in rats was much smaller (61). enhancement rather than an inhibition (90). An inhibition in lung tumor incidence followed feeding high levels of ret inyl Vitamins acetate to rats given 2 intratracheal instillations of MCA (15). The appearance of squamous carcinomas was Variation in the level of the vitamin B complex in the diet increased in lung tissue fragments treated with MCA and from the minimum required to keep the animals healthy to 9 implanted i.m. into syngeneic BALB/c mice (91). A failure times the level did not influence the yield of mammary to protect against carcinogenesis has been observed for tumors in DBA mice or of induced skin tumors in C3H or vitamin A in the induction of neurogenic tumors by DBA mice (102). Diets low in vitamin B complex had little, nitrosomethylurea and of squamous cell carcinomas of the if any, inhibitory effect on skin tumor induction in mice (8). bladder epithelium and liver tumors by dibutylnitrosamine Nevertheless, in specific situations, changes in the level of (81). certain vitamins may alter the carcinogenic response. The utility of vitamin A as an anticarcinogenic treatment Vitamin A. A deficiency of this vitamin leads to squa is problematical in view of those experiments producing mous changes in the respiratory and lower urinary tracts enhancement. Besides the lysosomal labilization reported (32, 114). The influence of this deficiency on carcinogenesis by Shamberger (83), Hill and Shih (33) have shown that 14 has not been studied, possibly because of the difficulty in vitamin A derivatives inhibited the metabolic activation of maintaining the health of the test animals. However, there B(a)P and other polycyclic aromatic hydrocarbons by liver has been interest in the apparent protective effect of high microsomes. The extent of inhibition varied with the levels of this vitamin since Chu and Malmgren (12) first derivative. It is clear that only further critical experimenta indicated that it protected against hydrocarbon-induced tion can clarify the present confusion. tumors. Feeding 0.5% vitamin A palmitate to hamsters Thiamine (Vitamin B1). This vitamin is destroyed by

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Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 1975 American Association for Cancer Research. D. B. Clayson thiamase present in bracken fern. When rats were fed dried tions (34, 37, 66, 84) are suspect, as the body weight of the bracken fern (33% of the diet), all the animals developed rats was not recorded. Liver tumors induced by 3- intestinal tumors, and 2 of 22 developed bladder tumors. methoxy-4-aminoazobenzene and its N-methyl derivative When a supplement of thiamine (2 mg weekly) was were inhibited by the incorporation of 0.5% cupric oxyace provided, the intestinal tumor incidence was unaffected, tate in the diet. The excess copper did not, however, affect whereas bladder tumors were induced in more than 50% of the incidence of ear duct tumors. The rats in the different the rats. There were no differences in average daily food groups consumed equivalent amounts of food (24). In a intake up to 6 months and no significant differences in further small experiment, it was shown that the same level survival rates (65). of cupric oxyacetate did not affect induction of skin tumors Riboflavin (Vitamin B2). Riboflavin inhibited formation by painting 3-methoxy-DAB (25). In diets containing either of hepatic tumors induced by DAB (36). It is an essential I ppm copper (deficient) or 800 ppm copper (excess), little constituent of certain cofactors of detoxifying enzymes (52) difference was found in the induction of liver tumors by and is considerably less effective against the 3'-methyl de FAA, although the incidence of tumors of other sites was rivative. Riboflavin analogs (7-ethyl-8-methyl- and 8-ethyl diminished ( 11). An earlier experiment failed to show that 7-methyl- l0(D-ribityl)-iso-alloxazine) are more effective copper affected 2-fluorenylamine carcinogenesis (29). than the parent compound against 3'-methyl-4-dimethyl DMN-induced kidney were frequent on a cop aminoazobenzene and 3'-methyl-4'-ethyl-4-dimethylamino per-deficient diet but were absent on an excess copper-con azobenzene (41). taming diet ( 11). However, the latter induced toxicity and Pyridoxine (Vitamin B6). A deficiency of pyridoxine reduction in body weight, and thus interpretation of these protects the rat liver from injury by FAA and permits the observations is difficult. There is a need for further critical animals to survive longer and thus to develop bladder observations in this area. tumors (48). The pyridoxine deficiency may influence Selenium. An essential trace element, selenium, on feed tryptophan metabolism (see above). ing at toxic levels, has given rise to hepatomas (57). These Ascorbic Acid (Vitamin C . Because of its ability to may be a consequence of cirrhosis due to levels of 5, 7, or 10 inhibit hyaluronidase, ascorbic acid may strengthen the ppm ammonium potassium selenide or, possibly, because of ground substance of the tissues. This has been postulated to a chance carcinogenic contaminant in the diet. An attempt inhibit cell proliferation and led to the suggestion that a very to repeat this observation cannot be considered adequate, high intake of ascorbic acid may aid in cancer prophylaxis because of the failure to report on controls (105). (10). This idea requires confirmation. Selenium is a powerful antioxidant and may therefore be Ascorbic acid reduces to nitrogen oxides. expected to inhibit carcinogenesis (see below). Clayton and It thus inhibits the in vivo and in vitro nitrosation of Baumann (14) reported a reduced liver tumor incidence at secondary and tertiary amines, amides, and ureas to form 20 weeks when 3'-methyl-4-dimethylaminoazobenzene was potently carcinogenic nitrosamines and nitrosamides fed to rats for the 1st and 3rd 4-week period of the (53—55).This action of ascorbic acid assumes considerable experiment, and when a diet containing 5 ppm selenium importance in of the use of nitrite as a food preserva instead of the basal diet was fed in the 2nd 4-week-period. tive and because certain drugs may be readily nitrosated (26, This effect was confirmed and body weight data were given. 44). Some , e.g., milk, have been shown to retard the Shamberger (82), using sodium selenide or selenate, showed nitrosation reaction (23). that selenium supplementation had, at best, a weak and inconsistent effect on polycyclic aromatic hydrocarbon Inorganic Constituents induced cutaneous cancer in mice. No significant effects were obtained with MCA painting; the use of DMBA and When the proportion ofa balanced mineral supplement in croton oil or croton resin gave variable results while, with the diet was altered, the incidence of naturally occurring B(a)P, fewer tumors were obtained. With FAA, higher mammary tumors and hepatomas, or of induced skin levels of selenium (2.50 and 0.50 ppm) apparently protected tumors in DBA mice was not affected, provided isocaloric against tumors as compared with rats given toxic selenium diets were used (103). Nevertheless, specific alterations in deficient diets (0. 10 and 0.00 ppm) (3 1). Body weights the levels of certain constituents of the mineral mixture may unfortunately were not discussed, and therefore the signifi have a profound effect on carcinogenesis. cance of this observation is in doubt. The effect of dietary Iodine. Iodine deficiency, or the administration of goitro selenium is obscure. gens, may lead to thyroid tumors. In the presence of a carcinogen such as FAA (3), or of thyroid irradiation (19), Enzyme Inducers and Antioxidants high yields of malignant thyroid tumors may be obtained. Goitrogens or iodine deficiency lead to a lowering of thyroid The alteration in the relative levels of metabolizing hormone levels in blood with a consequent homeostatic enzymes, known as induction, may be brought about by a increase in the levels of thyroid-stimulating hormone. This, wide variety of substances, including certain polycyclic if continuous, results in thyroid adenomas and, with a aromatic hydrocarbons, quinones, chlorocarbons, and bar carcinogenic stimulus, in thyroid . biturates. These substances, whether carcinogens or not, Copper Salts. In excess, copper salts have been shown to may profoundly influence carcinogenesis induced by an delay azo dye hepatocarcinogenesis. The earlier observa other agent (1, 16, 49), but will not be discussed here as they

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Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 1975 American Association for Cancer Research. Nutrition and Experimental Carcinogenesis are the subject of another paper in the symposium (112). Table 3 The antioxidants provide a similar group of chemicals A comparisonoftumor incidenceandotherdiseasesperUXICharlesRiver whose effects in the diet have been extensively investigated. COBS rats fed diets containing 10. 22, or 51% casein or given a choice diets°ModerateTumorsbSevereorbetweenthese The number of lung adenomas induced in female strain A mice by either diethylnitrosamine or 4-nitroquinoline I- oxide was significantly reduced by feeding BHA or ethox severe%Tumor myocardialproteinbearers°types)nephritisfibrosisProstatitis1026294<1522293818410512839391812Choice6291563862(allglomerulo yquin (108). BHA and BHT inhibited the formation of DMBA-induced forestomach tumors in female HA/ICR mice, mammary tumors in female Sprague-Dawley rats, and adrenal necrosis and general toxicity in rats (109). In further studies on strain A mice, BHA was given from 3 weeks before treatment with the carcinogen to the end of the experiment. The number of lung tumors/mouse induced by a From Ref. 76. B(a)P, DMBA, urethan, and mustard was reduced. b For 100 rats. On feeding dibenz(a,h)anthracene, DM BA, or 7-hydroxy methyl-12-methylbenz(a)anthracene in diet, fewer lung tumor-bearing animals and fewer tumors/mouse were 10, 22, or 51% casein in the diet; the other was offered a found in the presence of BHA (110). FAA carcinogenesis choice of these diets in separate feeding pots. The rats in the was likewise inhibited by BHT, but not by a different type of latter group each consumed different proportions of the 3 antioxidant, p-phenylenediamine (106), and BHT delayed diets. This group developed significantly more benign, but the appearance of rat liver tumors induced by DAB and not malignant, tumors, severe glomerulonephrosis, severe reduced the level of protein-binding (27). These antioxidants myocardiofibrosis, and prostatitis, than those rats that provide one of the more consistent and hopeful examples of received one of the other diets (Table 3). The significant carinogenesis inhibition. Their mode ofaction remains to be excess of lesions was reported to remain even after correc elucidated, but Wattenberg (1 11) has postulated that BHA tion for latency, age-specific morbidity rates, population and BHT may act partly through an enzyme-inductive effect size, and length of life. Although the rats given a free choice and partly through their antioxidant properties. of diet had an elevated body weight, this was not enough to explain the differences. The significance of these results is, Discussion as yet, unclear. Nevertheless, if the actual choice of diet, even on a genetically determined basis, influences tumor This review emphasizes the extent to which changes in incidence, this has considerable importance in the human nutrition may affect the incidence of tumors induced by situation. even the most potent carcinogens. The overriding factor is The most clearly understood effects of alteration in the dependence of the yield of many tumor types on the nutrition in experimental carcinogenesis are on the meta caloric value of the diet or on body weight. Although this bolic activation of chemical carcinogens. In order to permit fact has been established for many years, it is apparent that conclusions from animal experiments to be applied to man, some investigators have not realized its significance in there is a necessity for the effects of diet on other facets of determining the influence of other dietary changes on cancer the carcinogenic process to be elucidated. formation. The other important factor in the study of the effect ofdiet on chemical carcinogenesis is to avoid too high References a level of carcinogen, which may obscure more subtle changes induced by certain dietary modifications. I. Arcos, J. C., Conney, A. H., and Buu-Hoi, N. G. Induction of Microsomal Enzyme Synthesis by Polycyclic Aromatic Hydrocar Under appropriate conditions, changes in the nutritional bonsof Different Molecular Sizes.J. Biol. Chem., 236: 1291-1296, state of test animals may considerably alter the incidence of 1961. tumors. If the same is true for man, it is pertinent to inquire 2. Berg, J., Howell, M., and Silverman, S. Dietary Hypotheses and whether some tumors which appear to be influenced by Diet-Related Researchinthe Etiology of Colon Cancer.Health Serv. environmental factors are dependent on the nutritional Rept., 88:915-924, 1973. status of the population, rather than on exposure to 3. Bielschowsky,F. Tumours of the Thyroid Produced by 2-Acetyl tissue-specific carcinogens. For example, in aminofluoreneand Allyl-thiourea. Brit. J. Exptl. Pathol., 25: 90-94, the United Kingdom is more prevalent among the lower 1944. income groups. 4. Bollag, W. EffectsofVitamin A Acid (NSC-122758)in Transplanta Certain aspects of nutrition and experimental cancer ble and Chemically InducedTumors. Cancer ChemotherapyRept., 55:53-58, 1971. require further study. The effect of food has been 5. Bollag, W. Prophylaxis of Chemically Induced Papillomas and largely ignored, with the exception ofthe possible formation Carcinomas of Mouse Skin by Vitamin A-Acid. Experientia, 28: of carcinogens in heated fat (63). Also, some individuals, 1219-1220,1972. from an early age, have a choice in the type, as well as the 6. Bollag, W. H. Prophylaxis of Chemically Induced Benign and quantity, of food which they consume. An experiment Malignant Epithelial Neoplasmsby Vitamin A Acid (Retinoic Acid). designed to study this (76) consisted of feeding Charles EuropeanJ. Cancer,8: 689-693, 1972. River COBS rats on 1 of 4 regimens. Three groups received 7. Boutwell, R. K., Brush, M. K., and Rusch, H. P. The Stimulating

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